Intracellular protein tyrosine phosphorylation is regulated by extracellular stimuli, such as cytokines, to control cell growth, differentiation and functional activities. This signaling mechanism depends on the interplay of protein tyrosine kinases, which initiate signaling cascades through phosphorylating tyrosine residues in protein substrates, and by protein tyrosine phosphatases (PTPases) that terminate signaling via substrate dephosphorylation. Chemical compounds that modulate the activity of protein tyrosine kinases or phosphatases can induce cellular changes through affecting the balance of intracellular protein tyrosine phosphorylation and redirecting signaling.
Among the approximately one hundred PTPases encoded in the human genome, two PTPases in particular, Src homology protein tyrosine phosphatase 1 (SHP-1) and SHP-2, may be attractive targets for developing novel anti-cancer therapeutics. Based on its negative regulatory role in immune cells and cytokine signaling, SHP-1 may be inhibited by small molecules to augment anti-cancer efficacy of immunotherapy or cytokine therapy. Additionally, because SHP-2 is an oncogenic molecule in human malignancies and a mitogenic signal transducer, inhibitors of SHP-2 may also be expected to inhibit tumor cell growth.
So far, few clinically usable inhibitors of PTPases have been reported despite extensive efforts in the last decade to identify them. Although a number of chemicals that broadly inhibit PTPases are known (e.g. sodium orthovanadate, pervanadate, and iodoacetic acid), their value as therapeutic agents has been limited due to their non-selective action resulting in toxicity in vivo.